Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, California, United States of America.
PLoS One. 2012;7(7):e40164. doi: 10.1371/journal.pone.0040164. Epub 2012 Jul 6.
Fibroblast growth factor 21 (FGF21) is a potent metabolic regulator, and pharmacological administration elicits glucose and lipid lowering responses in mammals. To delineate if adipose tissue is the predominant organ responsible for anti-diabetic effects of FGF21, we treated mice with reduced body fat (lipodystrophy mice with adipose specific expression of active sterol regulatory element binding protein 1c; Tg) with recombinant murine FGF21 (rmuFGF21). Unlike wildtype (WT) mice, Tg mice were refractory to the beneficial effects of rmuFGF21 on body weight, adipose mass, plasma insulin and glucose tolerance. To determine if adipose mass was critical for these effects, we transplanted WT white adipose tissue (WAT) into Tg mice and treated the mice with rmuFGF21. After transplantation, FGF21 responsiveness was completely restored in WAT transplanted Tg mice compared to sham Tg mice. Further, leptin treatment alone was sufficient to restore the anti-diabetic effects of rmuFGF21 in Tg mice. Molecular analyses of Tg mice revealed normal adipose expression of Fgfr1, Klb and an 8-fold over-expression of Fgf21. Impaired FGF21-induced signaling indicated that residual adipose tissue of Tg mice was resistant to FGF21, whilst normal FGF21 signaling was observed in Tg livers. Together these data suggest that adipose tissue is required for the triglyceride and glucose, but not the cholesterol lowering efficacy of FGF21, and that leptin and FGF21 exert additive anti-diabetic effects in Tg mice.
成纤维细胞生长因子 21（FGF21）是一种有效的代谢调节剂，其药理学给药在哺乳动物中引发葡萄糖和脂质降低反应。为了阐明脂肪组织是否是 FGF21 抗糖尿病作用的主要器官，我们用重组鼠 FGF21（rmuFGF21）治疗具有脂肪特异性表达活性固醇调节元件结合蛋白 1c 的小鼠（Tg），从而减少体脂（脂肪营养不良小鼠）。与野生型（WT）小鼠不同，Tg 小鼠对 rmuFGF21 对体重、脂肪量、血浆胰岛素和葡萄糖耐量的有益作用无反应。为了确定脂肪量是否对这些作用至关重要，我们将 WT 白色脂肪组织（WAT）移植到 Tg 小鼠中，并对这些小鼠用 rmuFGF21 进行治疗。移植后，与 sham Tg 小鼠相比，WAT 移植 Tg 小鼠对 FGF21 的反应性完全恢复。此外，单独给予瘦素治疗足以恢复 Tg 小鼠中 rmuFGF21 的抗糖尿病作用。对 Tg 小鼠的分子分析显示，Fgfr1、Klb 在脂肪中的表达正常，并且 Fgf21 的表达过度增加了 8 倍。受损的 FGF21 诱导信号表明，Tg 小鼠的残余脂肪组织对 FGF21 有抗性，而 Tg 肝脏中观察到正常的 FGF21 信号。这些数据表明，脂肪组织是 FGF21 降低甘油三酯和葡萄糖的必需条件，但不是降低胆固醇的必需条件，并且瘦素和 FGF21 在 Tg 小鼠中具有相加的抗糖尿病作用。
